The reported incidence of acute kidney injury (AKI) varies from 5% in all hospitalized patients to 30-50% in intensive care units. Following acute injury, the kidney possesses a remarkable, but not inexhaustible capacity to repair itself. The factors stimulating this repair, and the source and role of autocrine, paracrine and/or endocrine growth factors in mediating the epithelial proliferation and repair remain uncertain. Numerous studies have indicated that infiltrating cells play an important role in the initiation and propagation of the tubule dysfunction and structural injury. The role of macrophages is of particular interest because they can exhibit distinctly different functional phenotypes, broadly characterized as proinflammatory (M1 or classically activated) and tissue reparative (M2 or alternatively activated) phenotypes. Macrophage infiltration is seen within one hour of reperfusion in ischemia/reperfusion models. These macrophages infiltrating early after ischemia/reperfusion injury have a distinct phenotype consistent with inflammatory or M1 macrophages. Macrophages are one source of proinflammatory cytokines such as IL-1, IL-6 and TNF-? that are detected following AKI. Depletion of monocytes prior to ischemia/reperfusion injury provides significant functional and structural protection. In contrast, there is increasing evidence that monocyte-derived cells may play an essential role in tissue repair in other organs and recent data suggest an important role in repair following acute kidney injury. We propose that there is an important role for resident macrophages and dendritic cells to mediate recovery from acute tissue injury. Resident macrophages and tissue dendritic cells demonstrate significant overlap in surface marker expression with M2 macrophages. The overall questions to be addressed are: What are the relative roles of infiltrating macrophages vs. resident macrophages and/or dendritic cells in recovery from AKI and what are the signals and mechanisms by which these monocyte-derived cells promote renal epithelial cell repair? To answer these questions, we propose three specific aims: Specific Aim I will determine the mechanisms by which renal macrophages/dendritic cells increase in response to acute kidney injury; Specific Aim 2 will determine the role of resident macrophage/dendritic cell phagocytosis of apoptotic cells (Efferocytosis) in promoting epithelial regeneration after AKI; Specific Aim II will determine mechanisms by which resident macrophages/dendritic cells stimulate epithelial cell regeneration. We propose that these studies will provide new and important insights into mechanisms of renal epithelial repair following acute injury and may lead to development of new treatment modalities for AKI, which are greatly needed.